Degradation of The Receptor for Advanced Glycation End Products (RAGE) - A Novel Mechanism in Lung Epithelial Cell Injury

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This application is for a Ruth L. Kirschstein National Research Service Award (NRSA) entitled “Degradation of The Receptor for Advanced Glycation End Products (RAGE) by FBXO10 – A Novel Mechanism in Lung Epithelial Cell Injury”. I am a physician in pulmonary and critical care medicine at the University of Pittsburgh. I am applying for this award to acquire advanced training in molecular physiology and cell biology, as well as new training in translational research methods and regulatory science, to develop my career as a physician scientist focused on the study of Acute Lung Injury. The main objective of my proposal is to determine how a novel RAGE degradation pathway in lung epithelial cells modulates severe lung injury. RAGE is a cell membrane receptor enriched in lung epithelia, and contributes to epithelial cell injury by weakening attachment to the extracellular matrix (ECM) and amplifying inflammatory signals in response to circulating ligands encountered in excessive inflammatory conditions such as Acute Respiratory Distress Syndrome (ARDS). Our preliminary data indicate that RAGE is degraded in lung epithelial cells in a mechanism dependent on the post-translational modification of ubiquitination. Furthermore, we have preliminarily identified a novel ubiquitin-transferring subunit termed FBXO10 responsible for targeting RAGE for degradation, and also show that RAGE is degraded in response to a ligand elevated in ARDS, CpG DNA. The aims of this study are: 1.) To determine if RAGE is ubiquitinated and degraded in lung epithelial cells by the E3-Ligase subunit FBXO10, and 2.) To determine the mechanism and biologic effect of RAGE degradation in pulmonary epithelial cells. These studies will provide insight into a novel pathologic model whereby RAGE degradation, regulated by FBXO10 mediated protein ubiquitination, controls epithelial cell detachment and excessive inflammation. FBXO10 mediated ubiquitination and degradation of RAGE may contribute to the histopathologic phenotype of “diffuse alveolar damage” characteristic of ARDS by promoting epithelial cell detachment from the ECM. Thus, modulating RAGE degradation may be a novel strategy to render epithelial cells more resistant to injury and contribute to an unmet need in novel ARDS therapies. This project will provide me advanced skills in molecular physiology and cell biology, and I will be trained in translational research methodologies and regulatory science to strengthen my development into an independent investigator. My work will be completed within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which is dedicated to the development of physician scientists. I have committed mentoring from our Division Chief Dr. Rama Mallampalli as well as a PhD cosponsor in Dr. Bill Chen. Additionally, my mentoring committee includes Dr. Janet Lee, MD – an expert in innate immunity and host defense, and Dr. Bryan McVerry – a translational scientist and member of the Acute Lung Injury Center of Excellence in charge of the clinical ALI program.